Cirrhosis of the liver is a serious pathological manifestation of alcohol abuse. Although effects of ethanol on various aspects of hepatic function have been studied extensively, the specific causes of alcoholic liver disease are not understood. One proposed mechanism is that lipid peroxidation resulting from free radical-mediated events is involved in the disease process. In support of this hypothesis, preliminary experiments have established that carbon-centered free radicals are generated in livers of rats administered ethanol acutely and chronically. The intensity of radical generation was increased if the rats were fed diets in which the fat content was increased to simulate that of the average U.S. diet. The working hypothesis for the proposed studies is that the radical may be associated with the process which results in liver injury caused by chronic ethanol consumption. This research will determine mechanisms by which ethanol exposure leads to radical formation. Inhibitors of pertinent enzyme systems will be utilized to establish whether acute hepatic injury occurs as a result of high levels of ethanol or acetaldehyde; or whether other reactive metabolites may be generated during ethanol metabolism. The physiological consequences of the ethanol-associated radicals will be investigated by assessing the functional integrity of the liver under conditions which intensify radical formation. For example, indicators of lipid peroxidation, levels of reduced and total glutathione, hepatic triglycerides, and metabolic flux rates in perfused livers and isolated hepatocytes will be utilized to assess hepatic function in rats exposed to ethanol. This research will also characterize nutritional, physiological, and pharmacological interventions which may potentiate or antagonize hepatic damage related to ethanol exposure. In addition, experiments will be designed to establish the identity of the radical detected in preliminary experiments, as well as other radicals that may be induced during ethanol feeding. The long-term goal of this research is to utilize EPR spin-trapping techniques that have been developed in our laboratories to trap free radicals in vivo and investigate the roles that free radicals may have in etiology of alcoholic liver disease. If the mechanism of the disease process could be better understood, it may be possible to reduce or prevent hepatic complications of alcoholism, or to better plan therapy for seriously ill patients.